Methicillin-resistant Staphylococcus aureus (MRSA) of the sequence type 59 (ST59) and ST398 lineages has emerged in hospitals and displayed a higher virulent potential than its counterparts ST5 and ST239. However, the mechanism of the host cell-pathogen interaction and specific determinates that contribute to the success of epidemic clones remain incompletely understood. In the present study, 142 S. aureus strains (ST59, ST398, ST239, and ST5) were selected from our 7-year national surveillance of S. aureus bloodstream infections (n = 983). We revealed that ST59 and ST398 had a higher prevalence of the protease-associated genes hysAVSaβ, paiB, and cfim and enhanced proteolytic activity than the other lineages. ST59 and ST398 showed a higher expression of RNAIII and psmα and greater proficiency at causing cell lysis than other lineages. Furthermore, ST59 and ST398 were strongly recognized by human neutrophils and caused more cell apoptosis and neutrophil extracellular trap degradation than the other lineages. In addition, these strains differed substantially in their repertoire and composition of intact adhesion genes. Moreover, ST398 displayed higher adaptability to human epidermal keratinocytes and a unique genetic arrangement inside the oligopeptide ABC transport system, indicating functional variations. Overall, our study revealed some potential genomic traits associated with virulence and fitness that might account for the success of epidemic clones. IMPORTANCE Considerable efforts have been exerted to identify factors contributing to the success of epidemic Staphylococcus aureus clones, however, comparative phenotypic studies lack representation owing to the small number of strains. Large-scale strain collections focused on the description of genomic characteristics. Moreover, methicillin-resistant S. aureus infections constitute 30% to 40% of S. aureus bloodstream infections, and recent research has elucidated highly virulent methicillin-susceptible S. aureus strains. However, comprehensive research on the factors contributing to the success of epidemic S. aureus clones is lacking. In this study, 142 S. aureus strains were selected from our 7-year national surveillance of S. aureus bloodstream infections (n = 983) accompanied by a rigorous strain selection process. A combination of host cell-pathogen interactions and genomic analyses was applied to the represented strains. We revealed some potential genomic traits associated with virulence and fitness that might account for the success of epidemic clones.